By contrast, in other studies Abl was found to restrain lamellipodia extension or inhibit initial cell attachment to the substrate. Abl family kinases have been suggested to regulate cell VEC-162 adhesion size and stress fiber formation ; Li and Pendergast recently reported that the Abl family member Arg, could disrupt CrkII-C3G 1345982-69-5 complex formation to reduce b1-integrin related adhesion formation. Thus, a complete understanding of how Abl family kinases regulate cell migration is lacking. In this study, we report that Gleevec, an Abl family kinase inhibitor that is used as a chemotherapeutic agent for leukemia, produces a profound change in the shape and migration of the rat Nara bladder tumor cells plated on collagen-coated substrates. Within 20 min of Gleevec treatment the majority of NBT-II cells develop a new D-shaped morphology and start migrating more rapidly and with greater persistence. The new morphology is characterized by stronger cellsubstrate adhesion and an increase in the size and number of discrete adhesions which at the leading margin turnover more rapidly. RhoA activity in Gleevec-treated cells was increased which, via myosin activation, led to an increase in the magnitude of total traction forces applied to the substrate. Upon Gleevec treatment, these chemical and physical alterations combined to produce the dramatic change in morphology and migration. Here, we show that inhibition of Abl family kinase activity with Gleevec produced a rapid and remarkable change in cell morphology and migration in which cells spread out a thin, extended lamella and migrated faster and with more persistence with some similarities to fish and amphibian keratocyte migration. In addition, this rapidly spreading, very thin lamella is similar to the rapid and extensive, ����pancake���� spreading of fibroblasts derived from Abl null mice. Associated with the Gleevec phenotype was an increase in RhoA activity, increased global cell adhesion strength, a pronounced change in adhesion patterns and an increase in total traction applied to the substrate. Abl family kinases have been reported to be located at cell adhesions. They are correctly positioned to regulate the reorganization of the cytoskeleton at sites of membrane protrusion and at
